Sitagliptin phosphate is glucagen like peptide 1 metabolism modulator, hypoglycemic agent and dipeptidyl peptidase IV inhibitor. Sitagliptin phosphate is currently marketed in the under the trade name of JANUVIA® in its monohydrate form. JANUVIA® is indicated to improve glycemic control in patients with type 2 diabetes mellitus. Its chemical name is 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3,-a]pyrazine phosphate monohydrate and the molecular Formula is C16H15F6N5O.H3PO4.H2O with a molecular weight of 523.32. The structural Formula of Sitagliptin phosphate monohydrate is:

PCT Publication No. WO 03/004498 assigned to Merck & Co., describes a class of beta-amino tetrahydro triazolo[4,3-a]pyrazines, which are potent inhibitors of DP-IV and therefore useful for the treatment of Type 2 diabetes. Specifically disclosed in WO 03/004498 is 7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-α]pyrazine hydrochloride. This application also discloses a method of introducing a chiral amine group using a chiral pyrazine derivative and to prepare Sitagliptin by Arndt-Eistert Homologation using t-butyloxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid. The process is shown in the scheme given below:

PCT publication No. WO 2004/087650 discloses the synthesis of Sitagliptin via the stereoselective reduction of methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate to produce the Sitagliptin intermediate (S)-methyl-4-(2,4,5-trifluorophenyl)-3-hydroxybutanoate. The said stereoselective reduction is performed by hydrogenation with H2 and (S)-BINAP-RuCl2 catalyst in presence of hydrochloric acid followed by inversion of stereochemical centre achieved by Mitsunobu cyclization of (3S)—N-benzyloxy-3-hydroxy-4-(2,4,5-trifluorophenyl)butyramide. The process is illustrated in the scheme given below:

PCT publication No. WO 2004/085661 discloses a process for the preparation of Sitagliptin by reduction of a substituted enamine. The process is shown in the scheme given below:

PCT publication No. WO 2009/084024 discloses process for the preparation of Sitagliptin and its pharmaceutically acceptable salts by resolving the amine with a resolving agent. Most of the time the said patent application describes the resolving agent as dibenzyl-L-tartaric acid. The said patent describes that the chiral purity obtained is only 85-90% that too after repeated recrystallizations. The process is shown in the scheme given below:

PCT Publication No. WO 2009/085990 discloses process for the preparation of Sitagliptin by using phenylalkylamine as a chiral handle for crystallization of diastereomeric mixture as shown below:

U.S. Pat. No. 8,476,437 B2 discloses the synthesis of β-amino acid derivatives and its salts by a novel process. The process comprises the reduction of a protected or unprotected prochiral β-amino acrylic acid or derivative there of, by using borane containing reducing agents at atmospheric pressure. The resulting racemic β-amino compound is resolved to a pure stereoisomer, specifically to (2R)-4-oxo-4-[3-trifluoromethyl)-5,6-dihydrol[1,2,4]triazolo[4,3-a]pyrazin-7 (8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine. The process is shown in the scheme given below:

The conventional methods for the preparation of Sitagliptin are problematic in that the use of catalyst like Ru is environmentally undesirable. The other syntheses mentioned above involve expensive chiral auxiliaries for the synthesis of desired enantiomers.
In light of the evolving and more rigorous requirement demanded of drug manufacturers and the prevailing disadvantages present with known synthesis, there is a need for an improved process for the preparation of Sitagliptin and its intermediates, which circumvents the likely formation of isomeric and other process related impurities, while ensuring a target Sitagliptin with optimum yield and purity.
In addition, the processes mentioned above have disadvantages in that the preparation through racemic diastereomers gives low yield.
Therefore, there is a great need for simple, eco-friendly, convenient, inexpensive and commercially viable process for the synthesis of Sitagliptin and its intermediates or its pharmaceutically acceptable salts, which alleviate the problems associated with aforementioned process.